Antibacterial drug resistance is a worldwide problem; new mechanisms of resistance emerge periodically and spread rapidly across the globe. The growing rate of antimicrobial resistance in clinical and non clinical settings poses significant threat to human health and animals, not only in India but also globally (Lancet Infectious Diseases, 9, 228-36, 2009). Each mechanism of resistance renders yet another class of antibiotics ineffective, ultimately resulting in fewer and fewer therapeutic options for patients. In fact, WHO now recognizes antimicrobial resistance as one of three greatest threats to human health (Clinical Infectious Diseases 50, 1081-1083, 2010). To address the issue of drug resistance, new chemotypes that target critical pathways in bacteria must be developed. We have identified a novel series of compounds that inhibit DNA Gyrase, a member of the DNA Topoisomerase family, and have broad spectrum antimicrobial activity.
DNA Topioisomerases are involved in the transient breaking and rejoining of DNA during replication, transcription and recombination. They are well conserved across the bacterial species and essential for viability. There are two classes of Topoisomerases, depending on whether they introduce single stranded (type 1) or double stranded breaks (type 2). DNA Gyrase and Topo IV are Type 2 Topoisomerases. Gyrase is responsible for the introduction of negative supercoils into DNA to allow fork progression during replication. It is a heterodimer consisting of two subunits of GyrA and two subunits of GyrB (Reviewed in Infectious Disorders—Drug Targets 7, 3-9, 2007).
Gyrase is a clinically validated target. Inhibitors of this target, the fluoroquinolones have been in use since the 1960s but suffer widespread drug resistance. Despite extensive research, newer generations of fluoroquinolones have not overcome resistance effectively. Recently two non-fluoroquinolone inhibitors of Gyrase have been described. One of them is NXL101 and the other is GSK299423. NXL101 belongs to a novel quinoline class with potent activity against gram-positive bacteria, including methicillin- and fluoroquinolone-resistant strains (Antimicrobial Agents and Chemotherapy, 52, 3339-3349, 2008). GSK299423 shows potent antibacterial activity against MRSA, fluoroquinolone resistant strains of S. aureus and Gram negatives such as E. coli, H. influenzae, M. catarrhalis and Klebsiella pneumoniae (Nature, 466, 935-942, 2010). While the compound potently inhibits DNA Gyrase, it has serious hERG binding liability (BMCL, 21, 7489-7495, 2011). Similarly, NXL-101 causes QT prolongation, which led to its discontinuation from clinical development (North American Journal of Medical Science, 4, 537-47, 2012). Nevertheless, the target continues to be attractive and novel chemotypes directed against the target will have significant clinical benefits, once proven to be efficacious and safe.